Preparation of famciclovir and other purine derivatives

Abstract

Purine derivatives, substituted at the 9-position, are prepared from a chloro substituted purine starting material, first making an alkyl substitution at the 9-position, then forming the desired esterified side chain, reducing this and hydrogenating the resultant diol prior to addition of alkyl carbonyl groups.

Description

FIELD OF INVENTION [0001] The present invention relates to the preparation of various 9-substituted purine derivatives, including famciclovir. BACKGROUND OF THE INVENTION [0002] Famciclovir (9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurin) is one of a number of compounds known to have useful antiviral activity and described, for example, in EP 141,927. Famciclovir has antiviral activity relevant for treatment of a number of viral infections, including herpes simplex, varicella-zoster and hepatitis. [0003] A number of different routes for preparation of purine derivatives such as famciclovir are known, including those described in EP 182,024, EP 141,927, EP 352,953, U.S. Pat. No. 5,684,153, U.S. Pat. No. 5,138,057, U.S. Pat. No. 5,917,041, U.S. Pat. No. 6,761,767, Geen et al. (2001) in Tet. Lett. 42(9) 1781, Harnden et al. (1989) in J. Med. Chem. 32(8) 1738, Hamden et al. (1990) in Nucleosides and Nucleotides 9(4) 499, Izawa and Shiragami (1998) in Pure and Applied Chemistry 70(...

AI Technical Summary

Benefits of technology

[0013] It has been found that employment of this step results in formation of the 9-substituted compound of formula V with high regioselectivity, the 9-substituted isomer being obtainable in specific embodiments of the invention at a ratio of 15-20:1 compared with the formation of the contaminating 7-substituted isomer. Hence, there is significantly reduced contamination by the unwanted isomer, reduced need for separation of the products of this reaction step and improved yield overall of the desired end product.

[0015] In operation of a method of the invention employing this step, there is high yield of the desired intermediate II and absence of a trans-acetylation side-reaction seen in prior art methods in which the corresponding hydrogenation step is carried out on a diester intermediate.

Problems solved by technology

However, a common problem associated with this process is lack of regioselectivity as the undesired 7-position isomer is generated simultaneously, reducing yield and requiring a separation step to remove this unwanted (inactive) isomer.

However, starting compounds 8 and 9 are not commercially available and have to be prepared separately.

Also, the overall yield for famciclovir is low, less than 30%.

But this process only produce famciclovir at about 18% overall yield.

Again, compound 11 used in this process is not commercially available and has to be prepared from nitrouracil.

Nevertheless, a common drawback in these methods is their lengthy procedure and overall low yield.

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